This application requests support for years 4-8 of a project whose goal is the identification of genes the loss of whose function is important in the development of basal cell carcinomas (BCCs), by far the most common human cancer. As in the retinoblastoma paradigm, there is a form of basal cell carcinoma in which, by comparison with the sporadic type, tumors arise at younger age, in greater numbers, and with autosomal dominant inheritance- the basal cell nevus syndrome (BCNS). During the past several years, we assessed linkage of the BCNS phenotype to more than 120 sites in a genome-wide search without identifying the location of the gene. Very recently, other investigators found such linkage at chromosome 9q, a site that we subsequently confirmed in our own kindreds We propose now to characterize more fully allelic loss at this site in BCCs and to search for the BCNS gene itself by a "positional cloning" strategy that relies heavily on a search for rearrangements disrupting the gene in BCCs or, preferably, in "constitutional" DNA from BCNS patients. Successful completion of this work should lead not only to fundamental insights into cutaneous carcinogenesis but also to understanding of the relationship of the tumors to the multiple phenotypic abnormalities of the inherited syndrome.